Not So Specialized After All: Genes Carry Out Different Repairs -- A Finding That Helps Clarify the Development of Cancer

In a finding that helps clarify the development of human cancer,scientists have demonstrated an additional way in which the samegenes can carry out repairs-or, if mutant, fail to carry themout -- to the body's DNA, the chemical of heredity that directseach cell.

Assistant professor Isabel Mellon of the University of Kentucky,Minoru Koi of the National Institute of Environmental Health Sciencesand Richard Boland of the University of California, San Diego,reported this work today in the April 26 issue of the journalScience.

"What makes this exciting is that people did not expect thatthe same two genes might make repairs in two different ways,along two different pathways," NIEHS research geneticistThomas A. Kunkel commented, "so this is a new and excitingfinding which provides more explanation of what may happen inthe development of cancer--and why people in some families aremore susceptible to the disease than others with the same exposuresto carcinogens."

As previously shown by Kunkel and others, DNA is constantly damagedby exposure to environmental chemicals and radiation, or by eventsthat occur naturally in the cells. "Mismatches" betweenthe twin strands of DNA occur as the cells replicate. The mismatchesare normally removed or repaired so that the cells functionproperly, but without such a repair, the mismatch remains andcan lead to disease.

For example, most people with a common form of hereditary colon-rectalcancer (hereditary non-polyposis colorectal cancer, or HNPCC) have mutations in one of their genes that result in their inability to perform this important DNA mismatch repair. Now, Mellon, Koi, Boland and others havedemonstrated in human cell lines that mutations of these samegenes can interrupt another type of DNA repair--a form of nucleotideexcision repair known as transcription-coupled repair.

"We think that defects in both mismatch repair and TCR areimportant, and it is possible that the TCR defect is a very earlyevent in tumor formations," Mellon said.

Transcription-coupled repair, or TCR, occurs mostly in genesthat are actively functioning. Without TCR, a cell has difficultyremoving damage. Malignant cells can form from these moderatelydamaged but living cells.

Mellon worked with NIEHS' Koi and others to add a normal mismatchrepair gene to a tumor cell line and show that it restored thetranscription-coupled repair. This provided evidence of a geneticcorrection and strengthened the evidence that mismatch repairand TCR overlap in the cell.

Deepak K. Rajpal and Gregory N. Champe, both of the Universityof Kentucky, Lexington, also participated in the research, whichprovides an additional explanation of how environmental chemicalscan cause cancer in some people, or in families, but not in otherswho are similarly exposed.

The results reported today were made a year after Mellon demonstratedin bacteria that the two genes mutS and mutL that are needed tocorrect mismatches and small insertion/deletion mispairs canalso result in deficiencies in transcription-coupled repair togenes that are actively functioning. Pointing also to the earlierwork by Richard Kolodner of the Dana-Farber Cancer Institute whichled to the discovery of the colon cancer gene, Mellon said thesestudies showed the value of work in bacteria: "Clearly weare different from bacteria, but many of the mechanisms are thesame."

The current work was funded by the National Institute of GeneralMedical Sciences, which, like NIEHS in Research Triangle Park,N.C., is one of the National Institutes of Health.

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